Ethynylation of 17-keto steroids (I) to produce the ethisterone type steroids (III) where the stereochemistry at C.sub.17 is 17.alpha.-ethynyl-17.alpha.-hydroxy is well known to those skilled in the art. Epiethisterone type compounds (II) have the 17.beta.-ethynyl-17.alpha.-hydroxy configuration at C.sub.17.
While the 17.alpha.-ethynyl-17.beta.-hydroxy or regular configuration is by far most common, the epi-configuration (17.beta.-ethynyl-17.alpha.-hydroxy) is known. Kanojia et al. in J. Org. Chem. 39, 2304 (1974) reported the epimerization of mestranol on an alumina column to epimestranol in 5% yield.
Kanojia et al. in J. Med. Chem. 22, 1538 (1979) reported ethynylating estrone 3-methyl ether with acetylene, potassium hydroxide in N-methylpyrrolidinone and obtained the corresponding expected 17.alpha.-ethynyl-17.beta.-hydroxy product (mestranol) in 87% yield and also obtained the epimeric 17.beta.-ethynyl-17.alpha.-hydroxy epimestranol in 13% yield by quantitative TLC. After column chromatography the epimestranol was obtained in 7% yield.
Kanojia in U.S. Pat. Nos. 3,983,112 and 4,022,892 discloses the epimerization of 17-acyl esters 17.alpha.-ethynyl-3,17.beta.-estradiol 3-ethers to 17.beta.-ethynyl-3,17.alpha.-estradiol by activated alumina.
Others have reported the C.sub.17 epimerization of the propargyl alcohol using heavy metals. For example, silver has been reported in the C.sub.17 isomerization by Westmizze et al. in Tetrahedron Letters 21, 2665 (1980), in European Pat. No. 53,845 and by Hofmeister et al. in Chem. Ber. 111, 3086 (1978).
European Pat. No. 53,845 and U.S. Pat. No. 4,440,689 also reported the isomerization of certain nitric and sulfonic acid esters with copper salts.
The process of the present invention is an epimerization process and produces the epi-configuration of ethisterone directly in greater than 25% chemical yield.